MRNA vaccines — what concerns do doctors and scientists raise?

Aim of the study: Adjuvanticity and delivery are crucial facets of mRNA vaccine design. In modern mRNA vaccines, adjuvant functions are integrated into mRNA vaccine nanoparticles, allowing the co-delivery of antigen mRNA and adjuvants in a unified, all-in-one formulation.

Results: However, careful design is necessary, as excessive adjuvanticity and activation of improper innate immune signalling can conversely hinder vaccination efficacy and trigger adverse effects. mRNA vaccines also require delivery systems to achieve antigen expression in antigen-presenting cells (APCs) within lymphoid organs. Some vaccines directly target APCs in the lymphoid organs, while others rely on APCs migration to the draining lymph nodes after taking up mRNA vaccines. This review explores the current mechanistic understanding of these processes and the ongoing efforts to improve vaccine safety and efficacy based on this understanding.

Aim of the study: The advent of mRNA vaccines represents a breakthrough in the realm of cancer therapy and the prevention of infectious disease. Nevertheless, traditional lipid nanoparticle (LNP)-based mRNA vaccines can accumulate in the liver post-intramuscular injection, posing a risk of hepatotoxicity and reducing efficacy.

Results: We construct a library of ionizable lipids with albumin-binding capacity as alternatives to traditional polyethylene-glycol-conjugated lipid. We identify an Evans blue-modified lipid-based LNP (EB-LNP) formulation that shows high in vivo expression, albumin-facilitated transport through intramuscular lymphatic vessels to the lymph nodes, high internalization by dendritic cells and low penetration into intramuscular blood vessels, thereby avoiding liver accumulation. EB-LNP-based mRNA vaccines demonstrate excellent antitumour and antiviral efficacy, resulting in strong cellular and humoral immune responses, including the robust activation of cytotoxic T lymphocytes and production of neutralizing antibodies post-vaccination. Overall, this system shows promise as an effective and minimally toxic platform for the development of mRNA vaccines with high efficacy and safety.

Aim of the study: The COVID-19 pandemic has severely affected adolescents. Safe and effective vaccines are pivotal tools in controlling this pandemic.

Results: AESIs were rarely reported but were more frequent after the second dose than they were after the first and the booster doses. Health impact was less common among adolescents after receiving BNT162b2 vaccine. Rare life-threatening AEFIs were reported across all doses in real-world studies. Our findings highlight the significance of enhancing national and regional vaccination programs to ensure public confidence.

Aim of the study: The concept of mRNA-based vaccines emerged more than three decades ago. Groundbreaking discoveries and technological advancements over the past 20 years have resolved the major roadblocks that initially delayed application of this new vaccine modality.

Results: The rapid development of nucleoside-modified COVID-19 mRNA vaccines demonstrated that this immunization platform is easy to develop, has an acceptable safety profile and can be produced at a large scale. The flexibility and ease of antigen design have enabled mRNA vaccines to enter development for a wide range of viruses as well as for various bacteria and parasites. However, gaps in our knowledge limit the development of next-generation mRNA vaccines with increased potency and safety. A deeper understanding of the mechanisms of action of mRNA vaccines, application of novel technologies enabling rational antigen design, and innovative vaccine delivery strategies and vaccination regimens will likely yield potent novel vaccines against a wide range of pathogens.

Aim of the study: The COVID-19 pandemic has highlighted the transformative potential of messenger RNA (mRNA) vaccines in biomedicine, thanks to their rapid design, scalable production, and strong immunogenicity. Nonetheless, their widespread adoption remains hindered by challenges related to sequence optimization, delivery efficiency, thermostability, and safety.

Results: Particular attention is given to the intrinsic adjuvant properties of mRNA molecules and their delivery vehicles, as well as strategies for incorporating exogenous adjuvants to modulate immune responses. Furthermore, the article provides a succinct overview of key preclinical and clinical advancements in mRNA vaccines targeting major infectious diseases (e.g., HIV, influenza, RSV, rabies) and tumor-associated antigens (e.g., HPV). This review is among the first to highlight breakthroughs in the application of AI for antigen screening, mRNA sequence optimization, lipid component selection, and vaccine stability prediction. Finally, the review addresses current platform limitations and proposes future directions for interdisciplinary collaboration, offering both theoretical insights and practical recommendations for the safe and effective implementation of next-generation mRNA vaccines.

Aim of the study: mRNA-based vaccines are emerging as a promising alternative to standard cancer treatments and the conventional vaccines. Moreover, the FDA-approval of three nucleic acid based therapeutics (Onpattro, BNT162b2 and mRNA-1273) has further increased the interest and trust on this type of therapeutics.

Results: In order to achieve a significant therapeutic efficacy, the mRNA needs from a drug delivery system. In the last years, several delivery platforms have been explored, being the lipid nanoparticles (LNPs) the most well characterized and studied. A better understanding on how mRNA-based therapeutics operate (both the mRNA itself and the drug delivery system) will help to further improve their efficacy and safety. In this review, we will provide an overview of what mRNA cancer vaccines are and their mode of action and we will highlight the advantages and challenges of the different delivery platforms that are under investigation.

Aim of the study: Seasonal influenza remains a major global public health challenge despite decades of vaccine development, underscoring the need for more effective and adaptable immunization strategies. The recently approved mRNA-1010 vaccine represents a promising advance by applying messenger RNA technology to a pathogen characterized by continuous antigenic drift.

Results: However, increased reactogenicity, particularly among younger adults, together with the need for continued post-marketing safety surveillance, highlights the balance between enhanced immune responses and tolerability. Beyond seasonal influenza, mRNA-1010 provides a foundation for next-generation respiratory vaccines, including combination formulations targeting influenza, SARS-CoV-2, and respiratory syncytial virus (RSV), while illustrating the broader potential of mRNA vaccine technology. At the same time, challenges related to manufacturing scalability, cost, cold-chain requirements, and global accessibility remain important considerations for widespread implementation. This perspective examines whether mRNA-1010 represents an incremental advance in influenza vaccination or a potential transformative milestone in respiratory immunization, while considering the continuing roles of alternative vaccine platforms in achieving optimal effectiveness, safety, and equitable global access.

Aim of the study: mRNA vaccines have become a clinically validated vaccine platform, as demonstrated by the success of COVID-19 vaccines such as Comirnaty and Spikevax, owing to their rapid design, manufacturing scalability, and capacity to induce in situ antigen expression.

Results: Despite remarkable progress, challenges related to formulation stability, long-term storage stability, safety and reactogenicity concerns, and durability of immune protection continue to hinder the broader application of mRNA-LNP vaccine platforms. This review provides an integrated overview of recent advances in mRNA-LNP vaccines, covering mRNA molecular engineering, LNP composition and delivery mechanisms, immune responses, clinical progress, and current developmental challenges. Furthermore, emerging strategies, including thermostable formulations, next-generation LNPs with improved targeting capability, emerging RNA platforms, and artificial intelligence-assisted optimization of RNA sequences and lipid materials, are discussed.